This invention relates generally to improvements in nuclear magnetic resonance analysis and specifically to the use of a true logarithmic amplifier to compress the dynamic range of a composite signal from a nuclear magnetic resonance receiver.
The development of nuclear magnetic resonance (NMR) spectroscopy for biological diagnostics was a discovery welcomed by biochemists who analyze living systems. An extensive discussion of this technique and its application to living systems may be found in copending applications Serial Nos. 904,000 filed Sept. 4, 1986, and 106,114, filed Oct. 7, 1987, both assigned to the assignee of the present invention, which are incorporated here by reference as if set forth fully.
It is well known that techniques for NMR spectroscopy rely upon identifying characteristic concentrations and distributions of protons in a test sample, which may be in vivo as well as in vitro, by subjecting the sample to pulses of electromagnetic energy while the sample is positioned within a uniform magnetic field. A typical such pulse used to analyze protons is at 50 MHz for 10 microseconds, although frequencies and pulse widths will vary. The embodiments of the invention described here are aimed at biological analysis, in which protons are of special interest. It should be emphasized, however, that organic constituents are only a part of the subject matter of NMR.
Data characteristic of the proton population received while the sample is under the influence of the magnetic field yield valuable information about living systems without the use of invasive examination techniques and methods. Where the sample is a live person or animal, many constituents are present in various concentrations, including a large concentration of water. The detection of millimolar or comparably small concentrations of a constituent in water can be very difficult.
One area in which this difficulty becomes significant is the detection of glucose levels in the bloodstream of a diabetic patient. The usual treatment for diabetes is single or multiple insulin injections daily. To determine if insulin is needed, blood is withdrawn from a patient and is tested for its glucose concentration, typically by a litmus indicator. If it is indicated, insulin is taken by the patient. This type of periodic testing can result in wide variations in detected glucose concentration over time, and treatment based upon this testing can create periods of high and low glucose concentration. Such variations can have physiological effects which may be adverse to the patient.
It is desirable to administer insulin periodically on demand and in response to changes in glucose levels. Such a technique is disclosed in A. Albisser, "Devices for the Control of Diabetes Mellitus", Proc. IEEE 67 No. 9, 1308-1310 (1979), in which a servo-controlled system continuously or continually withdraws blood from a patient. The blood sample is analyzed using a computer or microprocessor, the need for insulin is determined, and insulin is administered in response to that need. The main disadvantage of this system is that it is invasive, requiring the patient to be catheterized or the like to allow withdrawal of blood samples. The litmus test is similarly invasive, requiring the patient to be pricked repeatedly for blood samples.
In testing using techniques of NMR spectroscopy to determine the presence and concentration of glucose in the bloodstream of diabetic humans, the measurement of normal glucose levels produces a signal having a dynamic range of 37 B or more. This range is necessary because of the small concentration of glucose in body fluids. Such a dynamic range makes it difficult to identify the concentration of glucose accurately by linear receivers of the type conventionally used to detect nuclear magnetic resonance. Conventional linear receivers will tend to saturate and process the signal in such a way as to cause nonlinear mixing which results in intermodulation or other distortion of the processed output signal. Digitizing this distorted analog signal in a conventional analog-to-digital converter to produce an accurate reading is extremely difficult. Small processed signals are very difficult to digitize in the presence of an adjacent stronger processed signal. The resulting digitized signal that is fed to a digital computer is also affected because the word length for accurate digitization is restricted by the large dynamic range of the signal.
The present invention addresses the problems associated with the reception and analysis of a series of signals that are produced by NMR testing of samples in substances such as water or the like and that consequently have a large dynamic range. For example, NMR is a diagnostic technique widely used for medical diagnosis. In NMR, a test object is first subjected to a biasing magnetic field to align previously randomly oriented magnetic dipoles present in the nuclei. Other nuclei could be selected as the objects of interest, but protons are ordinarily the most useful to study in medically related investigations. The test object is then subjected to a pulse of a second magnetic field at a frequency calculated to increase the energy of selected nuclei by coupling to a characteristic resonant frequency of the nuclei. When the second magnetic field is turned off, the return of the nuclei to the first alignment releases energy which is detected, analyzed, and processed to form either a spectrum or a plot of free-induction decay. From the spectrum or plot of free-induction decay, the presence of particular molecular bonds can be observed and correlated with characteristic spectra for various molecules or materials. The concentration of that molecule or material can then be determined.
NMR systems have been used to analyze blood and to develop spectra of proton resonances. In such spectra, identifiable peaks are obtained for substances such as water, glucose and ethanol. In reported tests, blood serum has been taken from animals, placed in a container and excited to yield the proton spectra, which are then analyzed.
Existing NMR equipment, especially that used for medical Purposes, is generally large, complicated and expensive, and is therefore available only at hospitals, universities, and other similar research and test sites. The equipment therefore is not normally used for blood or body fluid analysis, as more convenient and less expensive alternatives are available, such as the invasive techniques described above.
The present invention applies a true logarithmic (log) amplifier to an NMR receiver to compress a received signal. This improves the dynamic range of the system and allows it to detect, identify and quantify both small and large concentrations of selected constituents simultaneously present in samples more accurately than before. A true log amplifier is defined here as an amplifier in which the output signal is proportional to the logarithm of the input signal and in which the input and output frequencies are the same, thus preserving information about the zero crossings of the signals. In contrast, some log amplifiers include envelope detection in processing the input signal, thus losing phase information which is important in NMR analysis.
Use of a log amplifier in signal processing systems is well known. In a series of patents assigned to Schlumberger Technology Corporation, New York, New York, the use of a log amplifier in a system to analyze and process electromagnetic signals is described. U.S. Pat. Nos. 4,063,151 (Suau et al.), 4,077,003 (Rau), 4,151,457 (Rau), 4,156,177 (Coates) and 4,338,567 (Coates) all teach various ways to use electromagnetic energy to determine the amount of bound and free water surrounding a bore hole so as to establish the porosity of the rock surrounding the bore hole. While a log amplifier is described as part of the operating hardware used to detect and analyze signals, no use is made of the log amplifier to improve the dynamic range or to compress the amplitude of the instantaneous signal.
In Russian Patent No. 873,187 (Yof et al.) the use of nuclear magnetic resonance to explore bore holes includes a log amplifier to process and analyze electromagnetic signals transmitted at the bore hole. This reference does not teach real-time signal compression or increasing the dynamic range of the received signal.
In U.S. Pat. No. 4,255,968 (Harpster) a flow indicator is taught in which a log amplifier is used to process a signal derived from the differences in readings of upstream and downstream temperature sensors. This produces a signal that is Proportional to the logarithm of the flow rate. This reference does not teach the use of the log amplifier to compress an incoming signal while preserving the phase information carried by that signal.
In using NMR spectroscopy for the purpose of analyzing body fluids for the presence of selected constituents, it is important that all phase information generated by the reflected NMR signal be preserved for analysis, because it is the phase shifts recorded in the signals that will indicate the presence of a selected constituent. This is true in general in any NMR analysis in which a solvent or other carrier is present in such relatively large concentrations as to swamp the NMR signal from a solute or other desired substance when the NMR signal is sent through a linear amplifier. An amplifier circuit used to detect and process these signals must include provision for preventing early saturation of the amplifier by the incoming signal. Such saturation will mean that during a portion of the signal its amplitude cannot be measured. This is important because quantification of the constituents present is based upon the ability of the system to compare the amplitudes of the signals for the water component of the body system with the amplitudes of the characteristic constituent signal for the body sample being tested and for a standard sample to which it is compared. All of these data must be stored in real time without distortion for later signal analysis. By compressing the dynamic range, the true log amplifier avoids saturation by the stronger signals (in particular, the water signal) while enabling the system to detect and preserve the amplitudes and phases of the other signals characteristic of the selected constituents.